Often, the ophthalmic medical and veterinary programs, it is desirable and important to provide for the slow release of a drug to the eye at a controlled and continuous rate over a prolonged period of time. In many programs such a rate of release should be substantially constant or have a zero order time dependence, that is, the rate of release is independent of time.
Different approaches have heretobefore been tried in ophthalmology to obtain a device for releasing drug to the eye at a controlled and continuous rate. One approach, which has received great attention, is to mix the drug with a carrier that is gradually broken down by eye fluids, the drug being released as the carrier disintegrates. Numerous carriers have been used in such systems, including soluble polymers such as gelatin and collagen. While these systems have provided a slower release of drug, a controlled and continuous release at a substantially constant release rate has not been obtained. One reason for this is that as the carrier disintegrates, the surface area of the dosage unit decreases, concomitantly exposing increasingly smaller quantities of the carrier to the surrounding eye fluids. This inherently results in a decline in the release rate over time. There has been little success in gaining control over drug release rate by this approach. More recently, in U.S. Pat. No. 3,618,604 there is disclosed an ocular drug delivery device that represents a substantial improvement over previously proposed drug devices and which devices can be successfully used for their intended purpose in the management of ocular medicine. But, the use of some of the polymeric materials set forth therein, for example, partially hydrolyzed polvinyl acetate because of its gel-like properties, has led to manufacturing difficulties and has not given the desired drug release rates in many instances.
In unrelated, non-ophthalmic fields, polymeric materials have been used for releasing non-ophthalmic substances. For example, in U.S. Pat. No. 3,310,235 a device is disclosed made of the material ethylene-vinyl acetate copolymer, as seemingly suitable for releasing volatile, organic and toxic phosphorous biocides by the process of physical evaporation. With this device, biocide release is achieved by evaporation from the surface, and if the ingredient is not sufficiently volatile at the temperature of use, the device has no practical value. Evaporation is achieved by using a woven cloth which acts as an evaporation surface. Release rate by evaporation is difficult to regulate and virtually impossible to control, as it is subjected to uncontrollable environmental conditions, the vapor pressure of the substance, and the degree of saturation of the volatile substance in the environment. This type of clearance inherently defeats the basic purpose of providing a device for ophthalmic use which requires release of drug at a controlled and continuous rate for a prolonged period of time as by the process of diffusion. Other incidental and non-therapeutic uses for ethylene-vinyl acetate copolymer are disclosed in U.S. Pat. No. 3,400,011 wherein the polymeric material is mixed with waxes and used for coating ingredients that are substantially released by the movement of external fluids into the coating, causing it to rupture and release the ingredient; in French Patent No. 1,489,490 as a thickener; and in French Patent No. 1,505,267 as a non-diffusional formless base for chewing gum. In our copending continuation U.S. patent application Ser. No. 705,479 filed concurrently herewith on July 15, 1976 and further identified by attorney Docket No. I.R. 176C-CONT., drug delivery devices including ocular devices manufactured from ethylene-vinyl acetate copolymers are disclosed for releasing drugs at controlled rates to animals. The devices claimed in said copending application are ocular devices and they are used for releasing drug to the eye. In this application, it has now been found that other ethylene-vinyl ester copolymers can be inventively used for manufacturing ocular systems designed in the form of ocular devices for releasing drug to the eye at a controlled rate over a prolonged period of time.